Synthesis of compounds having vitamin a activity



Patented July 1, 1952 sizirrrnis,1 sor" COMPOUNDS HAVING VITAMINAACTIVITY H '4 William Oroshnik, PlainfielmlN-r JQ,assignor to,

Ortho Pharmaceutical Corporation, alco'rporatlon of New Jersey NoD'rawing; Application March 1948',

W SerialNo. 13,338.

' silciaia si (crests-s11);

This; invention relates;- -to; compositionsoi mat-- ter andwtomethods ior preparing. the same. 'lfh s' inventionparticularly relates tocgppo'unds which arev derivatives" or; a -ionone and of, c-ethynyl-- e-ionol Y and? to; methods: of preparing, ;,th'e.,s aid derivatives;v

. It; is" an: obi ct or! this i ention" to; i pr pare.

compounds: to. be.- used,- asfintermediates', in the preparation of compounds namg am1an activity. .c

I l -It.is anotherobjectonthisinveutiomto prepare, compounds havingvitaminAactivity.

It i still. another: objector this. in'yentionfto prepare compounds, having the i same: number. oiv carbon atoms andthe sameconfigu'rati'on, with respect. to-carbon atoms a vitamiil others. a I

It is another and further object-of this. invenition to prepare compounds having vitamin A activity which are analogues of vitamin A.

It is still another object ofi this invention to prepare compounds having the same number of carbon atoms andthe same configuration with respect to carbon atoms as vitamin A ethers and the same number or hydrcgen;- atoms as vitamin A ethers.

Other objects of this invention will be apparent from the description following and from the ap-,

pended claims.

The chemical constitution and configuration of vitamin A has been known for" a number' of years, and heretofore it has been considered that vitamin A activity was inherent only in a structure which had five conjugated double bonds and that in this system of five conjugated-double bonds one must'be in the'ybeta positiouin the ionone-rin'g: c V

It has now been discovered that a compound containing only four conjugateddouble bonds and in which the double bond in the ionone ring is in the alpha position has vitamin A activity.

I have now discovered certain new derivatives of a-iOIlOIlE and of a-ethynyl -ionol and methods for their preparation; these derivatives may be prepared in excellent yields and they 'may he prepared free from impurities and stablelto distiilation;

It has been further discovered that the said derivatives of a-ionone and c-ethynyl-aloncl'may be hydrogenated and dehydrated; or isomerized, hydrogenated, and dehydrated; onhydrogenated,

isomerized, and dehydrated} to 1 torm l additionalderivatives which have vitamin'A-activitya In the practice of this invention, a-ethynylaa- CHr T I: E v Compound" y may 1 be reparedJin a numberof differ'ent--ways and in particular "by; reacting -ior 'oneiwith" calcium or lithiumacetylide in an inert s'olvefnt Iii a manner analogous to 1 that setlorth -in my- Patent No; 2425, 201,"filed septelfibr 11,1945; and

issued August 5, 1947; and in my copending application Serial No., 655,607, filed March 19, 1946, now Patent No; 2,472310. Sodium and potassium may. also; ice-used in. this reaction but the yield of Compound I is'low.

In the practice'of'this invention an acetylenic carbinol,

Compound II in which R is a hydrocarbon radical, is prepared by a first reaction between e-ethynyl-a-ionol and a reagent such as a metal alkyl in which the metal is a member of the first group, preferred reagents being methyl lithium and butyl lithium, or a metal alkyl in which the metal is a member of the second group such as zinc or magnesium. When zinc is the metal, the reagentmay be a zinc dialkyl such as dimethyl zinc or an alkyl zinc iodide such as methyl zinc iodide, and when magnesium is the metal, the reagent may be a dialkyl magnesium such as dimethyl magnesium or a Grignard reagent such as ethyl magnesium bromide. The Grignard reagent is preferred.

The reagent may be considered as having the following general formula: (R') IMY, in which R is a hydrocarbon radical such as methyl, ethyl,

benzyl, and the like; a: is an integer not greater than two; M is a metal having a valence not greater than two, and Y is a halogen if :c is one and the valence of the metal is two; but Y is nonexistent if M is a metal having a valence of one or if M is a metal having a valence of two and :c is two.

The product of this first reaction is represented by the formula,

in which M, Y, and R have the same significance L as above; but in which Y and Rifl'are nonexistent w if M is a metal having a valence of one, B. is nonexistent if M is a metal having a valence of two and Y is a halogen, and Y is nonexistent-'1 if M is a metal having a valence of two and R" In the preferred embodiment MY is MgBr and R is nonexistent 'or' is a hydrocarbon radical.

M is a metal having a valence of one and Y and R are nonexistent. In the single preferred practice orembodiment, MY isM'gBr'and R is nonexistent.

The product of the first reaction is reacted with an ether of a 1,4 halohydrin of isoprene represented by the formula,

in which Z is a halogen and R is a hydrocarbon radical, and in which, in the preferred form, R is CH3. This reaction is made in a solvent; satisfactory solvents .in clude;ether, benzene, tetrahydropyranpand tetrahydrofuran; The preparation' of this reagent, is described in my copending U.'S; application Serial No. 633,873, filed December-3,1945, now Patent No. 2,541,091.

' carom in 'which'M, Y. and B. have the same meaning -as'above and which in the preferred form MY is MgBr, R is nonexistent, and R is CH3.

Hydrolysis of the reaction mixture containing this compound in solution may be accomplished by any of'theus ualimethods' used for the hydrolysisof a Grigr'iardreaction mixture, such as treating with dilute acids; water, or' preferably with solution I of a'water-soluble ammemumsalt which has been made slightly alkalineJpH 7.5 to 9.0, by theadditlon of aqueous ammonium hydroxide. Upon hydrolysis of the reaction mixture, acompound is formed having the formula of Compound II. I

, After the hydrolysis, is complete, unreacted reagent containing 1 halogen is i removed, i and for this purpose, a' base is' 'employedJj-Inorganic bases such as alcoholic sodium hydroxide and potassium hydroxide or organic bases such" as diethylamine' may be used. The'following equations illustrate the process :for the preparation of CompoundII:

on, em

Compound 11' I ageoa'oea compoundnr' I intwhich'zRa i'saihydrocarbonzradical. Y I

In the: conversion or: @OHIPOlIiIdZi'II'Z" to; Com-s pound'vIII; catalytic aliydrogenatioirzmayrbewused; and-inithisrcase;itfihas beenifoundfithattpoisoned; palladium supportedion 'calciumzcarbonate; Raney nickel; oripoisonedrnaneyrnickel afe:satisfactory:- Raney nickel may:- be? satisfactorily." poisoned: by

a' cadmium. salt,- aszimr saltiwliicheforms;a zsclue ble compleic in: methyl: P alcohol iiwitlnamamine; piperidine; pyridine; thi'oui'iea, aminothiazoles'mr acombination? otizincracetatetr andi epiperidiire :1 however; Raney nickel poisonedibyra; combination of-" zin'c acetate: and: piperidinei?is? the: preferred catalysii It'lisiialsoilpossibleto re'duceisby chemical reagentsz-b'ut catalytic hydrogenation is prefrred:

Compound II may be distilled in ayacuumiin the absence of any traces-off acidic substances, and when so distilled, thereissubstantially no dehydration:duringjthe' distillationg Ifa trace of an aicidi'csubstanceispresentipartial or complet s dehydration-- of Compound w I! T may -.occur duringzth'edistillation. I a Compound: Himay be;- treatedrwith aistron'gly alkaline: substance'zsuchr as isodiumaorapotassium hydroxide :or alkoxidesineamaleohol, or aquaternaryP'ammoniumfl'hydroxide, at -roiom temperature or: above; and" thisbringvsabout; a rshi-ft sin'zrthe positionsofzthe 'bonds: Thesproductof-this?alkali treatment is? probably represented .byrtlierfollowingiormulay. a .1 3.5 e "12* Compound-IVY; i wherein" R is a hydrocarbon radical:

Thetriple'bcndin' Compound IVimeeidilkre duced by the same means asliave beem formerly discussed, and the resultant product is" probably (Jiompounli V may be sfm "ltaneously subjected to allylicrearrangement and dehydration in the presence of a dehydrating agent; Dehydrating agents which. have been found suitable'inelude an acidchloride inan organic base and specifl= cally benzoyl' chloride in' pyridine and acetyl chloride in dimethylaniline; glacial acetic acid; glacial aceticacid' and formic "acid; glacial acetic acid and potassium acetaterand aqueouslacetic acid. Dehydrationwitlitheabove' rea gents may lee-accomplished at'room'temperatureorslightly whereinR'is reaction mixture formed two layers.

above. Qtherfdj'eliydrationireagents found' suitablevv include toluene'su1fonic: acid; oxalic acid; glacial acetic acid}; catalytic quantitiesofiodine; plienyl isocyanat ,excess(}rig'nard* reagent; "and plienyl. isocyanate'j with" catalytic" quantities of Grignard reagent; Dehydration with" .these re agent's...is. accomplishedjin"benzene' at the boiling temperature off'benzene; Tlie:dehydratiori may alsobe. accomplishedi'by; heating in the presence oiexcess Grignard" reagent inta' mixture of xylene and, ether at a' temperature of"5'5 Cj: to {C5 The product or anyue rearrangement and dehy drationohasl vitamin'Kactiyity;

Compound III may be isomerizaed by" treatment at or above room temperature with a strongly alkaline substance such as sodium or potassium hydroxide or alkoxide in an alcohol, or a quater nary ammonium hydroxide, and the-*product 'of' the isomerization is probablytrepresented by the following formula, t v, .r p o I OH: on, V-

cm cm 1 '1 C n u s lz 1- a=hydrocarbon*radical.- 1 The alkali isomerized-product-ha's vitamin AactiyityL Compound VI is stable in -'the= absence of acidic substances an'd-may be dehydratedliynsing anyof the reagents for dehydration which area: listed above in connection with the dehydrationofCom pound V. The dehydrationsof Compound VI yields a material having vitamin A activity. 7 Compound mayalso";- be. dehydrated by methods similar to those employed for the dehydration of CompoundV and Compound VI.

In the following specific examples for carrying out the reactions outlined above, the compounds will be gre'fe'rred 'to b numbers used in tlie above description; w 7

The-following examplesare-given merely to illustrate specific ways in which the invention may be practiced; and it is; to be understood that the invention is not to be restricted or limited Preparation of. a-vethynyl-a ionol (Compound. I

- A two-litter round-bottom'fiaskequippedwlth v a; stirrerand-containing about-two thirds of a litter of 'lil' uid ammonia' wascooled inv a Dry Ice bath to about --40 on'bel'ow. Acetylene gas which had been ireed from acetone-by passage through"concentrated sulfurie'acidand dried by passage tli'rougli sodium hydroxide and calcium chlbridewja'sld into--'the-rea'ction flask. Eight grams (1;14'-'moles)'- of 'litliium metal, out into small pieces and-haying at-least' one freshly cut surface, were addedpiecemeal to-the ammonia. When all'of the lithium liad reacted; 350 cc. of dry ether were addedj'and this was followed-by theadditionofl92 grams (lmole) ofia-ionone b'y means of-ad'rop'pii'ig funnel The addition of a'cetylene'was stopped and "stirring was continued for three-hours at '-40 G;'to --35 *C. after which time grams I of ammoniumchloride were added. The flask was thenremoved 'fromthe cooling bath, and the-ammoniaw'as' evaporated as"thoroughlyaspossible cc; of-"ether and 500 cc: of water were then carefull'y added. The The ether layer wasremoved, washed with water, and dried over anhydrous potassium carbonate. The ether was evaporatedfand the residue was treated with '75 gm. (1 mole) or semicarbazide' and cc. of

glacial acetic. acid inlliter of methanol. After 24 hours the mixture waspoured into a large volume of.water and extracted with. petroleum ether. After drying overanhydrouspotassium carbonate; the petroleum ether extrajctw'as distilled under reduced pressure. The 2} fraction boiling at 89. C. and at 0.55 mm. of mercury pressurev had a refractive index of n *f 1.d937 and weighed 146 gm. Carbon and hydrogen analyses gave the following results'z. calculated for v j CisHssO ='a2.51%, H=10.16%; found, 'o= a2.5o%,

j v I i I EXAMPLEII- Preparation of the double Grignard' salt of a-ethynyl-a-ionol is then present in-the reaction mixturein-solution in the ether. This compound ma be'isolated from the reaction mixturein any convenient manner.

Condensation of a-ethynyl-a-ionol double .Griynard salt with 1-chloroe2smethyl-4-methorybutene-Z to form Compound II (methomy) 16 gm. (1.18 moles); of 1-chloro-2-methyl-4- methoxybutene-2 were added to the reaction mixture fromExampleII after; the-latter had been allowed to cool to roomtemperature. This addition was followed bythev addition of approximately 0.5'gm. of anhydrous cupric chloride as a catalyst. The mixture was stirred under ,a reflux condenser, heated to boiling, and keptat a boiling temperatureunder reflux for approximately six hours (after the second hour two, layerswere present) and then allowed to cool to room temperature andstirred for fifteen hours.

Thereaction mixture was hydrolyzed by first chillingthe stirred flask contents to -20 C. and then adding slowly and cautiously about 200 cc. of 30% aqueous ammonium-acetate solution containing:5% of 28% ammonia water. (30% aqueous ammonium chloridesolution or 5% aqueous acetic acid may also be used.a nd the procedure isthe same.) Thereaction mixture was allowed to come to room temperature and was stirred until all solid material had dissolved, then separated into two layers. The ether layer was treated to remove-any unreacted-halide reagent ,(methyl ether of the.1, d chlorohy'fdrin of isoprene). This was accomplished by adding 15 gm. -of 'cliethylamine to'the w'etethereal-solution of the crude condensation product. Since the'amine is higherboiling than ether. the ether was removed by evaporation at'reduced pressure and a further 15 gm. of diethylamine were added. The solution was allowed to stand at room temperature for 10 hours and was then poured into a large volume of water, whereupon an oil separated out and was extracted with petroleum ether. The petroleum ether solution was separated from the aqueous layer and was then'twashed withzwater several times and. finally with an aqueous-"solutionof sodium carbonate. "I'he'solution 'was dried. with anhydrous potassiumrarbonateor other suitable drying agent and filtered; the filtrate was concentrated underwacuum at room temperature. The concentrate consisted essentially of Com-' pound'II and was distilled at 0.001 mm. of mercury pressure. The product distilled at from?105 C.'to 115 C. and had a .refractive-index'at 20 C. of

1.5040; It showed only. end absorption in ultraat -room temperature under nitrogen for-forty eight hours. -The solution'after standing was poured into a large volume'of'water'and extra'ctedwith {petroleum ether." The: petroleum etherlayer was separated, dried; and'concent'rated under reduced pressure. A yellow oily liquid remained which was distilled at a pressure-of 0.001 mm. of mercury. A fraction boiled at 95 C. to 105 C. at this'pressure with a refractive index at 20 C. of 1.5223. 32.2 gm. of the product-were collected. This material had a tendency to polymerize to a glassy colorless resin during distillation. The ultra-violet spectrum of the distillate showed an absorption band with a maximum at 2280 A and a molecular coeflicient of extinction of 19,500.,5Carbonandhydrogen analyses gave the following resultsz -calculated for 0 11-13202, o=79.s9%,-.;1r=10.19%; iiound, c=79.7,5 H=.10.24%.,. 1.

EXAMPLE v Catalytic hydrogenation of Compound I V (methory) to form Compound Y (methomy) 10.3 gm. of Compound IV (methoxy), obtained in Example IV, were dissolved in 150' cc. of-methanol containing 0.4 gm. of zinc acetate and ,6 cc. of piperidine. Three grams of water-moist, roughly-blotted Raney nickel were added, and the mixture was hy rq enated under atmospheric pressure until the theoretical amountof hydrogen required. to convertthe acetylenic, bond to an ethylenic bQ d had been absorbed. The reaction mixture wasflltered poured into water, and-extracted with petroleum ether. The dried extract was concentrated, and the residue was distilled at a pressurezof 0.001 mm. of mercury. The bulk of the distillate weighed 10gm. and had arefractive index at ,20 -C. of 1.5091; it boiled at 107.? C. to, ,C;. ultra-Violet spectrum showed absorption, bands with inaximaat 20 70 EXAMPLE VI Dehydration of Compound V (methomy) byimeans of phenyl isocyanate and ferric chloride 10.5 gm. oi -Compound Vflmethoxy) obtained as in Example V were dissolved in 605cc. of dry benzene. 0.1 gm. of anhydrous ferric chloride'and 15cc. .of phenyl isocyanate: were added. The mixture was "then refluxedior"1%"liours. There was a copious precipitate of diphenylurea which was filtered oft, and the filtrate wastliendistilled at a pressure of 0.001 mm. of mercury. During the distillation there was some decomposition, and as a result'ofthi'sythe pressurefora-short period of time increased to 0.3 mm. of mercury. The distillation was continuedluntil no more' distillate was -obtained. The total distillatekwas dissolved in petroleum ether, filtered, and redistilled at 0.001 mm. of mercury pressure. The bulk of this distillate was collected at 110 C. and'had a refractive index at 20 C. of 1.5794. The*ultraviolet spectrum showed anabsorption band with maxima at 5 11.0.. AfandI3250 Q N'Ifandg'inolecular coeflicients' of extinction or "47210011121 "39,600

respectively.

. PLEYi Dehydration of Compound ll (methozcu) by means of para-toluene snlfonz'c acidrmonohydrate in glacial acetic acid 8.8 gm oj pompound (memo r-y) were dissolved in 50 cc. of'glacial aceticaci'd. "100 mg. of para-toluene sulfonic acid monohydratein 10 cc. of glacial acetic acid were added; andthe solution was -kept lat iroom-temperature for :onehalf hour and then at 373 C. for 2 ihours. It was poured into water, extracted with petroleum ether, and the petroleum ether solution was washed with dilute ammonium hydroxide, dried Hydrogenation of Compound II "(1nethoa:y) to -..:rorm-- ccmmmd. 1.11; .cmethowzll.

se es 21 ca me han e s-mi ta e-an .i1 ="o grams offmoist {,Raney mck'elwerjadded; "hydrogenationwasaccomplished at, atmospheric pressure andwas continued until the amount *of'hydrogen' necessary to no acetylenic bond to an ethylenic {bond absorbed. The"reaction ix'tlll' n u dint e ia dr xtr si d w ether. fi'lh'e dried extract'was concentr i 2356 gnirf of Compoiindil (methoxyfiwerejdisming. 3 i f {ha ,bie'en s ifi t re petroleum at ilmi tilledat Its ultra-violet spectrum showed an :(methoxy) .,fon in in 59. m. of CompoundIlI (methoxylasfobtained according to Example VIII wasadded' to-a solution of sodium 'methylate in' 'methanol obtained by reacting 68 "grams ii-sodium with' one liter 5 of methanol. The resulting summon was refluxed {poured into a large V, I The residual 001fmm. oi mercury h distilled at 1 m 0.

esults calculated Dehydration of compoun .meanwfphenyra 50 "ml. of phenyl iso'cyanate-and -ligroin, boilin'g poiht 6'8 C.' to 78. e to 5 gm. of Compound VI. heated to reflux C.),-, a continued iifor l /z hours; lli distilled, whereby the unreacted p cyanate was removed at a pressure off-12mm. of mercury; Thersresidue was then dissolved in 100cc. of 5% absolute ethanol, andthe/mixture' was then warmed at 40 C. for one'h'our in order to destroy any remaining phenyl .isocyanate. This solution was poured into water. and-:t he,oily material was extracted with petroleum ether: Thepetroleum ethersolutionwas driedgover gpo tassium carbonate, filtered, and -thewpetroleum ether was removed by evaporation under re The residue was distill'e'd-aat Dehydration .df- Compoand (memory) by means of para-toluene sulfonic acid "benzene 5.4 gm. of Compound VI (methoxy) 'were'dissolved in 100 cc. of dry benzene. 25 mg. of paratoluene sulionic ,acid .monohydrate were, added, and the mixture was refluxed under a water separator for one-half hour, during which timeabc'ut 30% .of .thethepretical amount'of waterfwas ol dented in thetrap." "The reaction mixture was then poured into water and extracted with petroleum ether. The extract was washed "with 'a efra'ctive index-"at.

dilute solution :01 potassium carbonate, dried over potassium carbonate, and concentrated under vacuum until all benzene had vbeen removed. The ultra-violet absorption spectrum of this concentrate showed maxima. at 3100 A and .3220 A and molecular coefiicients of extinction atthese wavelengths of 29,700 and 27,000 respectively.

Dehydration of Compound VI (methoaw) by a means of iodine in benzene gm.--'o f Compound VI (methoxwllwere dissolved in IOOI cc. of 'dry benzene containing 50 mg. of dissolved iodine, and the mixture was Tre fluxed under a water separator for one-half hour and then concentrated under vacuum. The con-- centrate was added to 100- cc. of 3% methanoli-c sodium hydroxide, and the mixture was refluxed one-half hour. This treatment removed all organically bound iodine. The mixture was then poured into water and extracted with petroleum ether; the extract was dried over potassium carbonateconcentrated under acuum and distilled at a pressure of 0.001 mm. -The bulk of the distillate wascollected between 105C. and 115v C. as aheavy yellow oil; it weighed 4.4 gm. and had .a refractive .index at C. of 1.5632. Its ultraviolet absorption spectrum showed maxima at 3100 A and 3250 A and molecular coefficients of extinction at these wavelengths of 33,300-a'nd 28,000 respectively.

Many quantities and detailsof procedure may be varied substantially without. departing from the principles of this invention and it is therefore to be understood that the scope of the patent granted on this invention is not to be limited otherwise than necessitatedby the scope of the appended claims. g i I ,Whatisclaimedimy a .0 1. The method comprising ,hydrogenating a compound 01' the formulaon. on, 1

H 0111' CH: v on=on-o-cEo'-on,- :=icH-cm-o-R H CH:

in which R is an alkyl radical, to produce a compound of the'formula inwhich R is an alkyl radical.

CHI CH:

hydrogenating a a at te H OH:

in which R is an alkyl radical.

4. A novel compound of theiormula 5. A q el compound otthe formula CHI inwhich R'is an alkyl radical; 5 I if 6, A'novel compound of the formula f OH; OH:

'7. A 'novel compound ,oi the iormula" ....CH: CH

CHI

in which A is-selecteddrom the group consisting oi the radicals. i-CEC-if-Lliiid. .CH=CH-..-, and -in which R is an alkyl radical. V

. 8. :The method comprising lreacting a-ethy nyl-a-ionol with. a reagent;.-selected from the group consisting- 0: R'Li, RMgX, RiZnX. RzMg, and R'zZn, in which R is a lower alkylradical and X is halogen, to produce anintermediateot the-formula cmom I V NYE H CH in which M is a'metal selected the group i t o M and/Zn halv n, and R is a loweralkyhradical, gbut in which Yand R. a e mneXi iani H ;i i9

nonexistant if M; is Mg or zn and is alower alkyl radicaL. I 1 7 A method according to claim'B inf which the reagent is R'Mgx.

10. A method accordinltogclaim' 1i "m'zai'ueh a 1.' in ee wmiJelm l ms i which the reagent is ethyl 3 ggesmm bfoifn'ide. 1 method comprising reacting t eth- 12. The

in which Z is a halogen and R is a yr v1r iono1 with afl l e'en j "se e e I em" t r n iiii s i f RIii, RL' E J R' DX. BfzM 'andRZn', in'whichR' isa lower 'allq'ylradical and X is a halogen, to produce an intermediate of the formula,

CH: I

- H CH3 I H, cH=oE-l J--cEc-MYR' j MYR in which M 'is a metal-selected mm *the group consisting of Mg, and Zn; Yisa halogen. and R is a lower-alkyl radical',"'but in which and R"'are nonexistant' if M is ,Li, Rf is 'nonexistant if Mis Mg oriZn and Y is 'ahalogen, and Y is nonexistant if M is Mg 1or1Zn, R; is a lower alkyl radical, and reacting the intermediate with a compound having the formula H t. Z-GH =CHCH-OR 'inwhi'ch is a halogen and R is "a lower alkyl radical," toproduce'a second intermediate of the formula i in which M, Y, R, and R have the same significance as above, and hydrolyzing the second intermediate'to produce a compound of the formula CH: OH:

in which M is a metal selected from the group consisting of Li, Mg, and Zn; Y is a halogen and R is v a lower alkyl radical, but in which Y and R' are nonexistent if M'is Li, R is nonexistent if M is Mg or Zn and Y is a halogen, and Y is nonexistent if M is Mg or Zn, R is a, lower alkyl radical, and reacting the intermediate compound havingthevformula with a stages I 31154 I g 0 I r i to produce asecond intermediate r; the formula t V. H

in which M, Y, R, and B have thesame significance as above, hydrolyzing'thesecond intermediate to producea compoundofthe formula CHI in which R has the same significance as above, and hydrogenating the acetylenic bond to produce a compound of theforrnula v H cmf on: p 1 ole-sorr cqzn crwom-cgcn-cnwon iv- 7 CH:

in which R has the same significance as above. 16. A method according toclaim 15 in which Z is chlorine and R is methyl. i

17. The method comprising reacting a-ethynyl- I a-iOIlOl with a reagent selected from the group consisting of R'Li, RMgx, RZnX, R'zMg, and

R'zZn, in which R is a lower alkyl radical and X is a halogen, to produce an intermediate of the Marat CH: 7 V

inflwhich M is a metal selected from the group consisting of Li, Mg; and Zn; Y is a halogen and R is a lower alkyl radical, but in which Y and R are nonexistant if M is Li, R is nonexistant if M is Mg or Zn and Y is a halogen, and Y is nonexistant if M'is Mg or Zn, R is a lower alkyl radical, and reacting the intermediate with a compound having the formula CHI in; z a a halogen'and R is s wer a1ky1 "rad a e at s we t rm d te i, ;.;1

ermian j Y;-?a', andR' have the same ignifica'nce as above, hydroly'zing the, second intermediate to produce a compoundof theformula was in whichjvllihas rtl eJsa'in'e.}signi fic an :e as above. and treating ,the hydrogenated product with a in which R has the same significance assabove.

18. The method comprising reacting a-ethynyla-ionol withva reagent selected from the group consisting of RfLi, RMgX, R'ZnX, ,R'sMg,

and RaZn, in which'R' is alower alkyl radical and X is a halogen, to produce an intermediate of the formula CH: CH:

g 1 l "'o zr cn-c -ogo-mm l (I i J, OMi R,

in which Ml .a metal selected from the .group iconsisting'oi Li, .Mg, and'Zn; Y is'la halogen and R, is a lower alkyl radical, but in which 'Y and R are nonexistant if M is Li, R is nonexistant if M is Mgor Zn and "Y a halogen,

and Y is nonexistant it M is Me or Zn, R is a lower alkyl radicaLand reactingthe intermediate with a compound-having the formula.

which'Z isla halogen .andfR is $1 loweralkyl rad formula, j

i ami e? as int te the in which ,M, R, and R have the .samelsigniiicance as above, ..hydrolyzing f the "second ."intermediate to produce a compoundoi *th'e joriniila CH: CH:

CHI

in which R :has the same significance .as above.

.hydrogenating theiaetylenic' bond to producea ,gompound oii thelfirinula" J j i CH: OH:

H CH:

CHI

OH CH:

cn=on o cikonfgg igon onwoa :16 in which R has the same. significance as above, treating the. hydrogenated product with astrongly alkalineprea'gem to produce :a compound .10! ther'foiml'lla L I in which R has the same significance as above. and dehydrating :to :produce a a compound having vitaminlA-factivity.

19'. "A method according to -claim 17in which the reagent is R MgX, Z is. .a ihalogen an'd 12B. :is a lowerialkylvradicalr A 7 2'0. ,A method according to a claim .18 {in which the reagentiis R'Mgxiz ls l a halogen, J and RLis a lower alkyl'radical.

21. A method according to claim "17 in which the reagent is ethyl magnesium bromide, Z is chlorine and R is-methyl.

,22. A vmethod according to claim 18 in which the -reagent is ethyl magnesium bromide, Z ,is chlorine andR is methyl. 7

23. A method comprising treating a compound of the formula in which R is .a .lowerv alkyl tradical. with a. strongly alkaline reagent'to produce a compound of the formula OH: CH:

which R h'as thesame significance 'as abovel V 24. A method according to claim 2'3 inwhich R-ismethyl. 7 r V r 25. A method according' toclaim 24"in which "the'strongly alkaline-reagentissodium methylate.

. f e hfl mp iising treating a-compound aofth'e formula I a in which R is a lower alkyl radical, with a strongly alkaline reagent to produce a compound of the formula '7. lkmethod-according to-claim .26 in which 17 28. A method according to claim 26 in which the strongly alkaline reagent is sodium methylate.

29. The method comprising treating a compound of the formula CH3 CH3 in which R is a lower alkyl radical, with a strongly alkaline reagent to produce a compound of the formula in which R has the same significance as above.

30. A method according to claim 29 in which R is methyl and the strongly alkaline reagent is sodium methylate.

31. The method comprising treating a compound of the formula CH3 CH8 H: CH3

I OH CH2 in which R is a lower alkyl radical, with a strong.- 1y alkaline reagent to produce a compound of the formula in which R has the same significance as above, and hydrogenating to produce a compound of the formula in which R has the same significance as above.

32. A method according to claim 31 in which the strongly alkaline reagent is sodium methyl ate.

. 18 33. The method comprising treating a compound of the formula in which R is a, lower alkyl radical, with a strong ly alkaline reagent to produce a compound of the formula in which R has the same significance as above, and hydrogenating to produce a compound of the formula in which R has the same significance as above, and treating the hydrogenated compound with an acidic reagent, whereby isomerization and dehydration occurs, to produce a compound having vitamin A activity.

34. A method according to claim 33 in which the strongly alkaline reagent is sodium methoxide.

WILLIAM OROSHNIK.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,369,157 Milas Feb. 13, 1945 2,369,159 Milas Feb. 13, 1945 2,369,161 Milas Feb. 13, 1945 2,369,164 Milas Feb. 13, 1945 2,382,068 Milas Aug. 14, 1945 2,412,465 Milas Dec. 10, 1946 2,425,201

Oroshnik Aug. 5, 1947 OTHER REFERENCES Oroshnik, Jour. Amer. Chem. Soc, vol. 67

(1945), page 1627. 

1. THE METHOD COMPRISING HYDROGENATING A COMPOUND OF THE FORMULA 